Abstract

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Cancer chronotherapy refers to a treatment method in which in vivo antineoplastic drug delivery is timed in relation to repetitive rhythms of drug related biological phenomena to produce the maximum health benefit and minimum harm to the patient. The goal of this work is to determine optimal drug delivery schedules based on modelling and systems biology, leading to tailored chronotherapeutics in individual patients. Within the TEMPO consortium, part of the EU's Sixth Framework Programme, Physiomics’ approach to chronotherapeutics is based on accurate mathematical models of the cell cycle, which mimic the cell cycle progression using circadian clock genes as its internal biological oscillator. Combining this pharmacodynamic (PD) model to a pharmacokinetic (PK) profile of the antineoplastic agents such as Seliciclib has lead to a complete PK-PD analysis framework for studying drug delivery and efficiency in various tissues and tumour. At the level of the single cell, the effects of a single dose of Seliciclib were evaluated after being administered at different stages of the cell cycle. The measured effects were either a slow down in the cell cycle or a complete cell cycle arrest. The simulation showed that optimal periods of administration of the drug could be established. When administered at various phases of the cell cycle, cell cycle progression was either barely affected, or arrested during the S phase or at G2/M transition. The various types of cell cycle arrest were already reported in experimental conditions. At the level of a tissue, Physiomics’ SystemCell cell population simulator was developed on the IBM “Blue C” supercomputer available at the Institute of Life Sciences, at University of Swansea. At the start of simulation, each cell is an individual instance of the model, and the whole population can be generated as a synchronous or as perfectly asynchronous tissue, sampled over a complete cell cycle. PK-PD simulations were performed to evaluate the impact of a single and multi-dose injection of Seliciclib in synchronous and asynchronous cell population models, as they can reflect the difference between healthy and tumour tissues. This study showed that specific administration times were crucial to obtain maximum effect (cell cycle arrest) in tumour tissue and minimum effect in healthy, synchronised tissue, paving ways for the determination of the chronotherapeutical delivery of Selicilcib.